Introduction: We evaluated the relationship between abnormalities of tubular architecture and tubulointerstitial nephritis antigen (TIN-ag) in juvenile nephronophthisis (J-NPH). Method: 16 J-NPH patients were examined. Nephrocystin-1, TIN-ag, and type IV collagen, Fas antigen, and the C5b-9 complement complex were stained by immunohistochemical methods. Results: Renal tubules of patients with J-NPH showed morphologic abnormalities of tubular basement membranes (TBM) and frequent apoptosis of tubular epithelial cells. Additionally, C5b-9 complement complex was deposited within the TBM in the absence of immunoglobulin deposition, suggesting complement-dependent TBM injury. Localization of TIN-ag in the TBM of J-NPH patients disclosed a partial defect or discontinuity in 14 of 16 patients, while type IV collagen immunoreactivity was relatively preserved. These findings suggest that in J-NPH patients, tubulogenesis is disturbed during nephronogenesis because of a defect in nephrocystin, an NPHP gene product. TBM defects induce further morphologic abnormalities such as cystic dilation of tubules; as tubular function impairment advances, the incomplete tubules may be injured by C5b-9 complement complexes, followed by apoptotic cell death. Conclusion: TIN-ag, which is important early nephrogenesis, lacks normal activity, and vulnerable and incomplete tubules with deficient TIN-ag expression are formed. Removal of these defective tubules by apoptosis combined with the C5b-9 complement complex could be the primary reason for progression to ESRD in J-NPH patients.